Huntington's disease (HD) is an inherited neurodegenerative disease that strikes in the prime of life and for which no disease-modifying treatments exist. The disease is caused by the expansion of a CAG repeat within the HD gene, leading to complex and extensive cellular dysfunction. The identification of validated cellular targets that impact the onset and progression of disease and a mechanistic understanding of these targets in HD systems are therefore critical to development of new and effective therapeutics. Mutant HTT (mHTT) and toxic fragments derived from the mutant protein are in a dynamic equilibrium poised to shift the protein homeostatic network from the appropriate balance of protein folding, misfolding, oligomerization and degradation to one in which that balance is disrupted. Upon disruption of this network, cellular proteins accumulate and degradation pathways become impaired. Our studies suggest that the E3 SUMO ligase, PIAS1, is a key modifier of this process and may act as an important regulatory switch in this dynamic equilibrium. In published findings, we identified PIAS1 as a novel modulator of both SUMO-1 and SUMO-2 modification and accumulation of mHTT protein in cultured cells. Further, reduction of the only PIAS in Drosophila delays expression of phenotypes caused by repeat expanded HTT, suggesting this enzyme may provide a selective therapeutic target. In addition to functioning as a SUMO E3 ligase, PIAS is implicated in regulating transcription of several pathways including proinflammatory cytokine signaling and the innate immune response, which is an emerging area of focus in HD. The communication and involvement between E3 SUMO ligases and protein clearance pathways are not well understood with respect to misfolded and accumulated proteins; therefore, understanding the behavior of the PIAS1 network in HD systems will contribute a crucial understanding as to its role in HD pathology. We hypothesize that PIAS1 is a key regulator of HTT SUMOylation and accumulation, that it can modulate HD pathogenesis and that it is a novel target for HD treatments. We propose to use a complementary set of cell based assays and in vivo studies to move forward our mechanistic understanding of PIAS1-mediated networks, and validate PIAS1 as a molecular target for HD drug development. Specifically, we will perform the following aims: Aim 1: Define the PIAS1 network in primary neurons and induced pluripotent stem cells. Aim 2: PIAS1 modulation in HD mouse models. Aim 3: Functional significance of PIAS1 domains in disease modifying pathways.